Blood urea nitrogen to serum albumin ratio as a new prognostic indicator in type 2 diabetes mellitus patients with chronic kidney disease

Chronic kidney disease (CKD) is often a common comorbidity in critically ill patients with type 2 diabetes mellitus (T2DM). This study explored the relationship between blood urea nitrogen to serum albumin ratio (BAR) and mortality in T2DM patients with CKD in intensive care unit (ICU). Patients were recruited from the Medical Information Mart database, retrospectively. The primary and secondary outcomes were 90-day mortality, the length of ICU stay, hospital mortality and 30-day mortality, respectively. Cox regression model and Kaplan–Meier survival curve were performed to explore the association between BAR and 90-day mortality. Subgroup analyses were performed to determine the consistency of this association. A total of 1920 patients were enrolled and divided into the three groups (BAR < 9.2, 9.2 ≤ BAR ≤ 21.3 and BAR > 21.3). The length of ICU stay, 30-day mortality, and 90-day mortality in the BAR > 21.3 group were significantly higher than other groups. In Cox regression analysis showed that high BAR level was significantly associated with increased greater risk of 90-day mortality. The adjusted HR (95%CIs) for the model 1, model 2, and model 3 were 1.768 (1.409–2.218), 1.934, (1.489–2.511), and 1.864, (1.399–2.487), respectively. Subgroup analysis also showed the consistency of results. The Kaplan–Meier survival curve analysis revealed similar results as well that BAR > 21.3 had lower 90-day survival rate. High BAR was significantly associated with increased risk of 90-day mortality. BAR could be a simple and useful prognostic tool in T2DM patients with CKD in ICU.


Inclusion and exclusion criteria
Patients admitted to the ICU for the first time were included in this study.Patients were excluded according to: (1) Less than 18 years old; (2) ICD code is not T2DM.(3) Without CKD.According to the KDIGO clinical practice guidelines, CKD was diagnosed that glomerular filtration rate (GFR) below 60 mL/min/1.73m 2 for 3 months or more 15 .(4) Missing BUN or serum albumin values; (5) Less than 48 h in ICU; (6) Missing data for more than 5% of patients.Finally, a total of 1920 patients were included in this study (Fig. 1).We had listed the top five diagnosed diseases and top five diseases that were first diagnosed in this population at admission to ICU (Supplementary Table 1, 2).

Statistical analysis
Patients were divided into three groups: BAR < 9.2, 9.2 ≤ BAR ≤ 21.3 and BAR > 21.3, according to the interquartile ranges (IQRs) of BAR value.Continuous variables were presented as mean ± standard deviations or IQRs, and classification variables were presented as totals and percentage (%).The chi-square test was used for classified variables between groups.The Wilcoxon rank-sum test was used for non-normally distributed continuous variables, and student t-test was used for normally distributed continuous variables.Univariate and multivariate cox regression were used to assess the independent factors associated with 90-days mortality, which presented as the hazard ratio (HR) and 95% confidence interval (CI).In order to reduce the impact of confounding factors, we constructed three Cox regression models to identify the potential clinical usefulness of BAR by including covariates with p values < 0.05 in the univariate Cox analyses or for importance of clinical concern.Kaplan-Meier survival analysis was used to determine the difference in 90-day mortality between the three groups.Stratification analyses was used to assess the association of BAR with 90-day mortality.P < 0.05 was considered statistically significant.The statistical analyses were performed using the Stata software version 16.0 (Stata Corp. LLC, TX, US).

Ethical approval and consent to participate
The informed consent was waived by the Institutional Review Boards of Beth Israel Deaconess Medical Center (Boston, MA) and the Massachusetts Institute of Technology (Cambridge, MA).The patient's information has been standardized and the project did not affect clinical care, so requirement for individual patient consent was waived.

Baseline characteristics
A total of 1920 patients were enrolled and were divided into the three groups: low-BAR group (BAR < 9.2, n = 486), mid-BAR group (9.2 ≤ BAR ≤ 21.3, n = 954), and high-BAR group (BAR > 21.3, n = 480).The number of man was significantly higher in the high-BAR group with lower proportion of hypertension.A higher proportion of CHF, CKD 4 stage and CKD 5 stage, along with higher levels of SOFA score, WBC, potassium, phosphate, creatinine, ALP, lactate and PTT in the high-BAR group; Patients with higher BAR had lower age, SBP, DBP, HGB, sodium, PaO 2, PNI, and eGFR (all p < 0.05) (Table 1).

BAR levels and outcome
Compared with low-BAR group (BAR < 9.2), patients with higher BAR had significantly higher the length of stay, in-hospital mortality, 30-day mortality and 90-day mortality (p < 0.05) (Table 2).

Prediction of 90-day mortality
The receiver operating characteristic (ROC) curve generated using the indicator variables (BAR, ALB, and BUN) were shown in Fig. 2. The AUC value of BAR was 0.708, which showed significantly higher AUC value than the ALB and BUN (p < 0.05).Similarly, the c-statistic of BUN, ALB, and BAR showed that BAR had the highest c-statistic (Supplementary Table 4).

Discussion
With the increasing prevalence of T2DM and CKD in worldwide, timely identification of prognostic risk factor is particularly important in clinical work.In our study, we found that higher BAR on admission to ICU was significantly associated with an increased risk of 90-day mortality in T2DM patients with CKD.And BAR could serve as an independent predictive factor of 90-day mortality.Further, the K-M curve also presented that the high BAR group had a worse prognosis.Our study was the first largest study to explored the relationship between BAR and prognosis in T2DM patients with CKD in the ICU.BUN is a nitrogen-containing compound that it is influenced by renal function, neurohormone, and sympathetic nervous activity.BUN is mainly filtered through the glomeruli and excreted through urine.When glomerular filtration function decreases, BUN concentration will increase.BUN can not only be used to estimate glomerular filtration function, but also to assess the body's nutritional status, low blood volume, protein metabolism and others 8 .Many studies have found that BUN was a powerful predictor of prognosis in patients with heart failure, and its efficacy was even better than GFR and serum creatinine 16,17 .A large study in China found that BUN levels were positively associated with the risk of developing T2DM in Chinese adults 18 .Studies in T2DM patients showed that the increased BUN level will significantly increase the risk of diabetes retinopathy and diabetes nephropathy 19,20 .Elevated BUN indicated poor prognosis for patients in the ICU 13,21,22 .In the ICU, T2DM patients with CKD had circulatory dysfunction and neuroendocrine system dysfunction, which further aggravated kidney injury.At this time, high levels of BNU may predict a worse prognosis for patients.ALB is not only a nutritional marker, but also plays an important role in anti-inflammatory, antioxidant and others aspects 23 .As an important antioxidant in plasma, ALB inhibits apoptosis of renal tubular cells by clearing oxygen free radicals 24 .It was found that ALB not only improves renal perfusion and glomerular filtration by prolonging renal vasodilation, but also selectively inhibits the expression of tumor necrosis factor-α-induced vascular cell adhesion molecule 1 and the activation of nuclear kB and monocyte adhesion in human endothelial cells to prevent kidney injury 13,25 .In T2DM patients, ALB level was negatively correlated with the incidence of diabetes retinopathy 26 .Besides, a study also showed that hypoproteinemia significantly accelerated the risk of renal failure in patients with diabetes nephropathy 27 .Low ALB level was caused by insufficient nutrition intake and a state of inflammatory stress in ICU patients.Numerous studies had suggested that hypoalbuminemia was a risk factor for poor prognosis in ICU patients [28][29][30] .
High BAR levels are caused by high BUN or low ALB.BAR has been proven to be a more reliable predictor than BUN or ALB.In our study, ROC curve also showed the AUC value of BAR was significantly higher than the ALB and BUN.Studies suggest that high BAR can significantly increase the mortality of patients with sepsis, acute myocardial infarction, acute pulmonary embolism, heart failure and others 11,21,31,32 .A study found that high BAR significantly increased in-hospital mortality and the incidence of AKI for patients with cerebral hemorrhage in the ICU 13 .Our study also found similar results.We found that when BAR > 21.3, patients' stay in the ICU, hospital mortality, and 30-day and 90-day mortality were significantly increased.After adjusting for confounders such as serum creatinine, CKD and others, elevated BAR was still positively associated with poor prognosis in patients undergoing cardiac surgery 33 .Similarly, in our study, after controlled for confounding variables by multivariate Cox regression analysis, we found that high BAR was an independent risk factor for 90-day mortality.Besides, in subgroup analysis, we demonstrated that BAR was an effective predictor of 90-day mortality in T2DM patients with CKD under various specific conditions.Therefore, in clinical practice, we may be able to reduce the BUN value by improving glomerular filtration rate (such as increasing renal perfusion by maintaining normal volume load), and also by increasing albumin (infusion of human serum albumin, etc.) to reduce BAR, thereby reducing the risk of 90 day mortality in patients.In routine clinical practice, BAR could be calculated easily and quickly, and is more stable and conducive to clinical application compared with a single indicator.
In our study, several limitations should be highlighted to interpret the results as follows: First, this study as a single-centric retrospective study, we couldn't avoid to selection bias.Second, the data used in the manuscript were recorded from 2001 to 2012, which were old.Third, due to the limited contents of this database, some unrecorded clinical information was missing, may affect the outcome.Fourth, this study only included BUN and albumin records of patients at their first admission, so that the prognostic impact of dynamic changes in BAR was still unclear.Finally, the underlying mechanism of BAR affected the prognosis could not be determined.www.nature.com/scientificreports/Therefore, it is necessary to establish a large multicenter prospective study to confirm the above results and further to investigate the mechanism.

Conclusion
A higher BAR was significantly associated with an increased risk of 90-day mortality.BAR could be served as a prognostic predictor for 90-day mortality in T2DM patients with CKD in ICU, due to its inexpensive and readily available nature.

Figure 1 .
Figure 1.Flow diagram of the study.

Figure 2 .
Figure 2. Receiver operating characteristic curves for the prediction of 90-day mortality.

Figure 3 .
Figure 3. Kaplan-Meier curve was used to evaluate the difference between BAR levels and 90-day mortality in T2DM patients with CKD in the ICU.In the Kaplan-Meier analysis, the log-rank test P value < 0.001.

Table 2 .
BAR level and clinical outcome.

Table 3 .
Univariate Cox regression analyses to assess risk factors associated with 90-day mortality in T2DM patients with CKD.

Table 5 .
Subgroup analysis of the associations between BAR and 90-day mortality.